Hsp70 and Hsp90 post-translational modifications and translating the chaperone code

Abstract

Molecular chaperones maintain proteostasis by assisting protein folding, stability, and activity. Heat shock protein 70 (Hsp70) and Hsp90 (Hsp90) are ATP-dependent chaperones essential for protein quality control, signaling, and stress adaptation. Their activities are controlled not only by co-chaperones, but also by dynamic post-translational modifications (PTMs). This review dissects phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and other PTMs of Hsp70 and Hsp90 across systems. These PTMs regulate the ATPase activity, localization, and interactions of the molecular chaperones with major implications in health and disease. The term “chaperone code” describes the PTM landscape that fine-tunes chaperone function. This code governs client fate, drug sensitivity, and stress responses. Importantly, combinatorial PTMs introduce regulatory complexity and flexibility, especially in cancer, neurodegeneration, and inflammation. The crosstalk between various PTMs and feedback loops add new regulatory layers to chaperone function. Additionally, these PTMs impact the function of the clients that are central in regulating specific cellular processes or pathways, such as transcription, autophagy, metabolism, and immune regulation. These pathways are usually affected in different maladies, such cancer, neurodegenerative, infectious and chronic diseases. Unlocking the chaperone code is essential for directing chaperone activity toward therapeutic benefit. This can be achieved by targeting enzymes that write, erase, or read the chaperone code, thereby offering new therapeutic strategies.